Macular degeneration is a clinical term that is used to describe a family of diseases that are characterized by a progressive loss of central vision associated with abnormalities of the Bruch's membrane, the choroid, the neural retina and/or the retinal pigment epithelium. In the center of the retina is the macula lutea, which is about ⅓ to ½ cm. in diameter. The macula provides detailed vision, particularly in the center (the fovea), because the cones are higher in density. Blood vessels, ganglion cells, inner nuclear layer and cells, and the plexiform layers are all displaced to one side (rather than resting above the ones), thereby allowing light a more direct path to the cones. Under the retina is the choroid, a collection of blood vessels embedded within a fibrous tissue, and the pigmented epithelium (PE), which overlays the choroid layer. The choroidal blood vessels provide nutrition to the retina (particularly its visual cells). The choroid and PE are found at the posterior of the eye.
The retinal pigment epithelial (RPE) cells, which make up the PE, produce, store and transport a variety of factors that are responsible for the normal function and survival of photoreceptors. These multifunctional cells transport metabolites to the photoreceptors from their blood supply, the chorio capillaris of the eye. RPE cells also function as macrophages, phagocytizing the tips of the outer segments of rods and cones, which are produced in the normal course of cell physiology. Various ions, proteins and water move between the RPE cells and the interphotoreceptor space, and these molecules ultimately effect the metabolism and viability of the photoreceptors.
Age-related macular degeneration (AMD), the most prevalent macular degeneration, is associated with progressive loss of visual acuity in the central portion of the visual field, changes in color vision, and abnormal dark adaptation and sensitivity. Two principal clinical manifestations of AMD have been described as the dry, or atrophic, form, and the wet, or exudative, form. The dry form is associated with atrophic cell death of the central retina or macula, which is required for fine vision used for activities such as reading, driving or recognizing faces. About 10-20% of these dry AMD patients progress to the second form of AMD, known as wet AMD.
Wet (neovascular/exudative) AMD is caused by abnormal growth of blood vessels behind the retina under the macula and vascular leakage, resulting in displacement of the retina, hemorrhage and scar formation. This results in a deterioration of sight over a period of months to years. However, patients can suffer a rapid loss of vision. All wet AMD cases are originated from advanced dry AMD. The wet form accounts for 85% of blindness due to AMD. In wet AMD, as the blood vessels leak fluid and blood, scar tissue is formed that destroys the central retina.
The most significant risk factors for the development of both forms are age and the deposition of drusen, abnormal extracellular deposits, behind the retinal pigment epithelium. Drusen causes a lateral stretching of the RPE monolayer and physical displacement of the RPE from its immediate vascular supply, the choriocapillaris. This displacement creates a physical barrier that may impede normal metabolite and waste diffusion between the choriocapillaris and the retina. Drusen are the hallmark deposits associated with AMD. The biogenesis of drusen involves RPE dysfunction, impaired digestion of photoreceptor outer segments, and subsequent debris accumulation. Drusen contain complement activators, inhibitors, activation-specific complement fragments, and terminal pathway components, including the membrane attack complex (MAC or C5b-9), which suggests that focal concentration of these materials may produce a powerful chemotactic stimulus for leukocytes acting via a complement cascade (Killingsworth, et al., (2001) Exp Eye Res 73, 887-96). Recent studies have implicated local inflammation and activation of the complement cascade in their formation (Bok D. Proc Natl Acad Sci (USA). 2005; 102: 7053-4; Hageman G S, et al. Prog Retin Eye Res. 2001; 20: 705-32; Anderson D H, et al. Am J Ophthalmol. 2002; 134: 411-31. Johnson L V, et al. Exp Eye Res. 2001; 73: 887-96).
Wet AMD is associated with choroidal neovascularization (CNV) and is a complex biological process. Pathogenesis of new choroidal vessel formation is poorly understood, but such factors as inflammation, ischemia, and local production of angiogenic factors are thought to be important. Although inflammation has been suggested as a playing a role, the role of complement has not been explored. A preliminary study of CNV has been shown to be caused by complement activation in a mouse model (Bora P S, J Immunol. 2005; 174: 491-497).
The complement system is a crucial component of the innate immunity against microbial infection and comprises a group of proteins that are normally present in the serum in an inactive state. These proteins are organized in three activation pathways: the classical, the lectin, and the alternative pathways (V. M. Holers, In Clinical Immunology: Principles and Practice, ed. R. R. Rich, Mosby Press; 1996, 363-391). Molecules on the surface of microbes can activate these pathways resulting in the formation of protease complexes known as C3-convertases. The classical pathway is a calcium/magnesium-dependent cascade, which is normally activated by the formation of antigen-antibody complexes. It can also be activated in an antibody-independent manner by the binding of C-reactive protein complexed with ligand and by many pathogens including gram-negative bacteria. The alternative pathway is a magnesium-dependent cascade which is activated by deposition and activation of C3 on certain susceptible surfaces (e.g. cell wall polysaccharides of yeast and bacteria, and certain biopolymer materials).
The alternative pathway participates in the amplification of the activity of both the classical pathway and the lectin pathway (Suankratay, C., ibid; Farries, T. C. et al., Mol. Immunol. 27: 1155-1161(1990)). Activation of the complement pathway generates biologically active fragments of complement proteins, e.g. C3a, C4a and C5a anaphylatoxins and C5b-9 membrane attack complexes (MAC), which mediate inflammatory responses through involvement of leukocyte chemotaxis, activation of macrophages, neutrophils, platelets, mast cells and endothelial cells, increased vascular permeability, cytolysis, and tissue injury.
Factor D may be a suitable target for the inhibition of this amplification of the complement pathways because its plasma concentration in humans is very low (1.8 μg/ml), and it has been shown to be the limiting enzyme for activation of the alternative complement pathway (P. H. Lesavre and H. J. Müller-Eberhard. J. Exp. Med., 1978; 148: 1498-1510; J. E. Volanakis et al., New Eng. J. Med., 1985; 312: 395-401). The inhibition of complement activation has been demonstrated to be effective in treating several disease indications using animal models and in ex vivo studies, e.g. systemic lupus erythematosus and glomerulonephritis (Y. Wang et al., Proc. Natl. Acad. Sci.; 1996, 93: 8563-8568).
Using single-nucleotide polymorphism (SNP) analysis of AMD patients, a Factor H genetic variant (Y402H) was found to be highly associated with increased incidence of AMD (Zareparsi S, Branham K E H, Li M, et al. Am J Hum Genet. 2005; 77: 149-53; Haines J L, et al. Sci 2005; 208: 419-21). Persons who are either homozygous or heterozygous for this point mutation of Factor H gene may account for 50% of AMD cases. Factor H is the key soluble inhibitor of the alternative complement pathway (Rodriguez de Cordoba S, et al. Mol Immunol 2004; 41: 355-67). It binds to C3b and thus accelerates the decay of the alternative pathway C3-convertase (C3bBb) and acts as a co-factor for the Factor I-mediated proteolytic inactivation of C3b. Histochemical staining studies show that there is similar distribution of Factor H and MAC at the RPE-choroid interface. Significant amounts of deposited MAC at this interface found in AMD patients indicate that the Factor H haplotype (Y402H) may have attenuated complement inhibitory function. It is speculated that Factor H (Y402H) may have a lower binding affinity for C3b. Therefore, it is not as effective as wild type Factor H in inhibiting the activation of the alternative complement pathway. This puts RPE and choroids cells at sustained risk for alternative pathway-mediated complement attack.
It had been shown that lack of Factor H in plasma causes uncontrolled activation of the alternative pathway with consumption of C3 and often other terminal complement components such as C5. In keeping with this finding, plasma levels of Factor H are known to decrease with smoking, a known risk Factor for AMD (Esparza-Gordillo J, et al. Immunogenetics. 2004; 56: 77-82).
Currently, there is no proven medical therapy for dry AMD, and no treatments available for advanced dry AMD. In selected cases of wet AMD, a technique known as laser photocoagulation may be effective for sealing leaky or bleeding blood vessels. Unfortunately, laser photocoagulation usually does not restore lost vision, but merely slows, and in some cases, prevents further loss. Recently, photodynamic therapy has shown to be effective in stopping abnormal blood vessel growth in about one third of wet AMD patients when treated early. In Visdyne Photodynamic Therapy (PDT), a dye is injected into the patient's eye, it accumulates in the area of vessel leakage in the retina and, when exposed to a low power laser, it reacts sealing off the leaking vessels. In addition to these two laser techniques, there are several anti-angiogenesis therapies targeting vascular endothelial growth Factor (VEGF) being developed for the treatment of wet AMD. However, only 10% treated patients show vision improvement.
In view of these inadequate treatments for wet AMD and the total lack of treatments available for advanced dry AMD, there is a clear need for the development of new treatments for this serious disease. Our invention provides a novel approach to treating this serious disease.